Genetic Variant JAG1:c.2916+26_2916+27dupTT (chr20-10641432-C-CAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_000214.3(JAG1):c.2916+26_2916+27dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0019 ( 0 hom. )

Consequence

JAG1
NM_000214.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.173

Publications

3 publications found

Variant links:

Genes affected

JAG1 (HGNC:6188): (jagged canonical Notch ligand 1) The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human jagged 1 is the ligand for the receptor notch 1, the latter is involved in signaling processes. Mutations that alter the jagged 1 protein cause Alagille syndrome. Jagged 1 signalling through notch 1 has also been shown to play a role in hematopoiesis. [provided by RefSeq, Nov 2019]

JAG1 Gene-Disease associations (from GenCC):

Alagille syndrome due to a JAG1 point mutation
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
Charcot-Marie-Tooth disease, axonal, Type 2HH
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
tetralogy of fallot
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

JAG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000181 (27/149262) while in subpopulation AFR AF = 0.000471 (19/40342). AF 95% confidence interval is 0.000308. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000214.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	JAG1	NM_000214.3	MANE Select	c.2916+26_2916+27dupTT		intron	N/A	NP_000205.1	P78504-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
JAG1	ENST00000254958.10	TSL:1 MANE Select	c.2916+27_2916+28insTT	intron	N/A	ENSP00000254958.4	P78504-1
JAG1	ENST00000901230.1		c.2916+27_2916+28insTT	intron	N/A	ENSP00000571289.1
JAG1	ENST00000913738.1		c.2910+27_2910+28insTT	intron	N/A	ENSP00000583797.1

Frequencies

GnomAD3 genomes

AF:

0.000168

AC:

AN:

149160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000423

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000665

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000742

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00192

AC:

2594

AN:

1353642

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1222

AN XY:

675884

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00205

AC:

AN:

30252

American (AMR)

AF:

0.000186

AC:

AN:

43050

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

24722

East Asian (EAS)

AF:

0.00

AC:

AN:

36984

South Asian (SAS)

AF:

0.000488

AC:

AN:

81886

European-Finnish (FIN)

AF:

0.000509

AC:

AN:

49090

Middle Eastern (MID)

AF:

0.000744

AC:

AN:

5374

European-Non Finnish (NFE)

AF:

0.00229

AC:

2354

AN:

1026078

Other (OTH)

AF:

0.00126

AC:

AN:

56206

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.262

Heterozygous variant carriers

316

632

949

1265

1581

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

240

360

480

600

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000181

AC:

AN:

149262

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

AN XY:

72804

show subpopulations

African (AFR)

AF:

0.000471

AC:

AN:

40342

American (AMR)

AF:

0.0000664

AC:

AN:

15068

Ashkenazi Jewish (ASJ)

AF:

0.000290

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5064

South Asian (SAS)

AF:

0.000212

AC:

AN:

4710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000742

AC:

AN:

67366

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00276

Hom.:

552

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.17

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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20-10641432-CAA-CAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over